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Phosphorylated TDP-43 pathology and hippocampal sclerosis in progressive supranuclear palsy

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Abstract

TDP-43 is characteristically accumulated in TDP-43 proteinopathies such as frontotemporal lobar degeneration and motor neurone disease, but is also present in some tauopathies, including Alzheimer’s disease, argyrophilic grain disease, and corticobasal degeneration (CBD). However, several studies have suggested that cases of progressive supranuclear palsy (PSP) lack TDP-43 pathology. We have therefore examined limbic regions of the brain in 19 PSP cases, as well as in 12 CBD cases, using phosphorylation-dependent anti-TDP-43 antibodies. We observed TDP-43-positive inclusions in five PSP cases (26%), as well as in two CBD cases (17%). The amygdala and hippocampal dentate gyrus were most frequently affected in PSP. Regional tau burden tended to be higher in TDP-43-positive PSP cases, and a significant correlation between tau and TDP-43 burden was noted in the occipitotemporal gyrus. Hippocampal sclerosis (HS) was found in 3/5 TDP-43-positive PSP cases, but HS was significantly more frequent in TDP-43-positive than TDP-43 negative PSP cases. Dementia was present in 13/19 (58%) of the PSP cases, in 4/5 TDP-43-positive cases, in all 3 TDP-43-positive cases with HS, in 1/2 TDP-43-positive cases without HS, and 7/14 cases lacking both. TDP-43 and tau were frequently colocalized in the amygdala, but not in the hippocampal dentate gyrus. Immunoblotting demonstrated the characteristic (for TDP-43 proteinopathies) 45 and 25 kDa bands and high molecular weight smear in the TDP-43-positive PSP case. These findings suggest that (1) although PSP is nominally a tauopathy, pathological TDP-43 can accumulate in the limbic system in some cases, and (2) TDP-43 pathology may be concurrent with HS.

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Acknowledgments

This study was supported in part by a research grant from the Uehara Memorial Foundation and Grant No. AG13854 from the National Institutes of Health. We thank Ms. M. Onbe (Department of Neuropsychiatry. Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences) for their excellent technical assistance, and the Parkinson’s Disease Society Brain Bank for making available tissue samples for this study. A part of this study was presented at the 111th annual meeting of the British Neuropathological Society in January 2010.

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Authors and Affiliations

  1. Neurodegeneration and Mental Health Research Group, Faculty of Medical and Human Sciences, School of Community Based Medicine, Greater Manchester Neurosciences Centre, Hope Hospital, University of Manchester, Salford, M6 8HD, UK

    Osamu Yokota, Yvonne Davidson & David M. A. Mann

  2. Neurodegeneration and Mental Health Research Group, Faculty of Medical and Human Sciences, School of Community Based Medicine, A V Hill Building, University of Manchester, Oxford Rd, Manchester, M13 9PL, UK

    Stephen Sikkink & Stuart Pickering-Brown

  3. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60619, USA

    Eileen H. Bigio

  4. Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan

    Osamu Yokota, Hideki Ishizu & Seishi Terada

  5. Zikei Institute of Psychiatry, 100-2, Urayasu-honcho, Okayama, 702-8508, Japan

    Hideki Ishizu

  6. Department of Psychogeriatrics, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo, 156-8585, Japan

    Tetsuaki Arai & Haruhiko Akiyama

  7. Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo, 156-8585, Japan

    Masato Hasegawa

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  1. Osamu Yokota
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  2. Yvonne Davidson
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Correspondence to David M. A. Mann.

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Yokota, O., Davidson, Y., Bigio, E.H. et al. Phosphorylated TDP-43 pathology and hippocampal sclerosis in progressive supranuclear palsy. Acta Neuropathol 120, 55–66 (2010). https://doi.org/10.1007/s00401-010-0702-1

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  • DOI: https://doi.org/10.1007/s00401-010-0702-1

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